Tetraploidy-linked sensitization to CENP-E inhibition in human cells,Molecular Oncology

当前位置： X-MOL 学术 › Mol. Oncol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Tetraploidy-linked sensitization to CENP-E inhibition in human cells
Molecular Oncology ( IF 5.0 ) Pub Date : 2023-01-23 , DOI: 10.1002/1878-0261.13379
Koya Yoshizawa ₁ , Akira Matsura ₁ , Masaya Shimada ₁ , Sumire Ishida-Ishihara _{1,

2} , Fuyu Sato ₁ , Takahiro Yamamoto ₁ , Kan Yaguchi ₁ , Eiji Kawamoto ₃ , Taruho Kuroda ₃ , Kazuya Matsuo ₄ , Nobuyuki Tamaoki ₅ , Ryuichi Sakai ₆ , Yasuhito Shimada ₇ , Mithilesh Mishra ₈ , Ryota Uehara _{1,

2}

Affiliation

Tetraploidy is a hallmark of cancer cells, and tetraploidy-selective cell growth suppression is a potential strategy for targeted cancer therapy. However, how tetraploid cells differ from normal diploids in their sensitivity to anti-proliferative treatments remains largely unknown. In this study, we found that tetraploid cells are significantly more susceptible to inhibitors of a mitotic kinesin (CENP-E) than are diploids. Treatment with a CENP-E inhibitor preferentially diminished the tetraploid cell population in a diploid–tetraploid co-culture at optimum conditions. Live imaging revealed that a tetraploidy-linked increase in unsolvable chromosome misalignment caused substantially longer mitotic delay in tetraploids than in diploids upon moderate CENP-E inhibition. This time gap of mitotic arrest resulted in cohesion fatigue and subsequent cell death, specifically in tetraploids, leading to tetraploidy-selective cell growth suppression. In contrast, the microtubule-stabilizing compound paclitaxel caused tetraploidy-selective suppression through the aggravation of spindle multipolarization. We also found that treatment with a CENP-E inhibitor had superior generality to paclitaxel in its tetraploidy selectivity across a broader spectrum of cell lines. Our results highlight the unique properties of CENP-E inhibitors in tetraploidy-selective suppression and their potential use in the development of tetraploidy-targeting interventions in cancer.

中文翻译：

人细胞中 CENP-E 抑制的四倍体相关敏化

四倍体是癌细胞的标志，四倍体选择性细胞生长抑制是靶向癌症治疗的潜在策略。然而，四倍体细胞在抗增殖治疗的敏感性方面与正常二倍体细胞有何不同在很大程度上仍是未知数。在这项研究中，我们发现四倍体细胞比二倍体细胞更容易受到有丝分裂驱动蛋白 (CENP-E) 抑制剂的影响。在最佳条件下，用 CENP-E 抑制剂处理优先减少二倍体-四倍体共培养中的四倍体细胞群。实时成像显示，在中度 CENP-E 抑制下，与四倍体相关的不可解决的染色体错位增加导致四倍体的有丝分裂延迟明显长于二倍体。这个有丝分裂停滞的时间间隔导致内聚疲劳和随后的细胞死亡，特别是在四倍体中，导致四倍体选择性细胞生长抑制。相反，微管稳定化合物紫杉醇通过加重纺锤体多极化引起四倍体选择性抑制。我们还发现，在更广泛的细胞系谱中，CENP-E 抑制剂的四倍体选择性优于紫杉醇。我们的结果突出了 CENP-E 抑制剂在四倍体选择性抑制中的独特特性及其在开发四倍体靶向癌症干预措施中的潜在用途。微管稳定化合物紫杉醇通过加重纺锤体多极化引起四倍体选择性抑制。我们还发现，在更广泛的细胞系谱中，CENP-E 抑制剂的四倍体选择性优于紫杉醇。我们的结果突出了 CENP-E 抑制剂在四倍体选择性抑制中的独特特性及其在开发四倍体靶向癌症干预措施中的潜在用途。微管稳定化合物紫杉醇通过加重纺锤体多极化引起四倍体选择性抑制。我们还发现，在更广泛的细胞系谱中，CENP-E 抑制剂的四倍体选择性优于紫杉醇。我们的结果突出了 CENP-E 抑制剂在四倍体选择性抑制中的独特特性及其在开发四倍体靶向癌症干预措施中的潜在用途。

更新日期：2023-01-23

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南